Is SIM1 p.Asp424= (c.1272T>C) pathogenic?

SIM1 p.Asp424= (c.1272T>C) is classified Likely benign in SIM1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-05-05). Ultra-rare (popmax 0.0164%, mid); Associated with SIM1-related disorder.

What condition is associated with SIM1 p.Asp424= (c.1272T>C)?

SIM1 p.Asp424= (c.1272T>C) is associated with SIM1-related disorder (ClinVar).

How common is SIM1 p.Asp424= (c.1272T>C) in the general population?

SIM1 p.Asp424= (c.1272T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

SIM1 p.Asp424=

c.1272T>C · rs139667045 · VCV3031473

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

SIM1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.76	GERP -1.7, phastCons 1
Overall
CADD	8.374	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00291% 47/1,614,000 alleles · ultra-rare exomes 46/1,461,786 · genomes 1/152,214 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00668%	14,962
European (non-Finnish)	0.00347%	28,780
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,058

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SIM1
Protein: p.Asp424=
Coding: c.1272T>C
MANE Select: NM_005068
dbSNP: rs139667045
Type: single nucleotide variant
Location: chr6:100393785 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70
Residue 424: the single-minded c-terminal domain; the 'disordered' region

Full SIM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SIM1-related disorder

Similar variants

SIM1 p.Asp424Gly Uncertain significance ★ ⚠ same residue
SIM1 p.Asp424Tyr Uncertain significance ★ ⚠ same residue
SIM1 p.Arg374Trp Uncertain significance ★★ ⚠ same condition
SIM1 p.Ser199Cys Uncertain significance ★★ same condition
SIM1 p.Gly480Ter Likely pathogenic ★ same condition
SIM1 c.-468+6T>A Uncertain significance ★ same condition
SIM1 p.Ala484Ser Uncertain significance ★ ⚠ same condition
SIM1 p.Asn608Asp Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/sim1-p-asp424 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown